HIF1α‐mediated AIMP3 suppression delays stem cell aging via the induction of autophagy

Abstract

Senescence in stem cells, which occurs as a consequence of chronic responses to the environment, defines the capacity of stem cells for proliferation and differentiation as well as their potential for tissue regeneration and homeostasis maintenance. Although stem cells reside under low oxygen pressure and the availability of oxygen is known to be a crucial determinant in their fate, the key modulators in stem cell aging and the underlying mechanism have yet to be unraveled. Human placenta‐derived mesenchymal stem cells (hpMSCs) were cultured under hypoxia (3% O2) or normoxia (21% O2) to investigate the key factors that regulate stem cell senescence under hypoxic conditions. RNA sequencing results suggested that the expression of aminoacyl‐tRNA synthetase‐interacting multifunctional protein 3 (AIMP3, EEF1E1), an aging inducer, in the hpMSCs was dramatically repressed under hypoxia with concurrent suppression of the aging marker p16INK4a. The hpMSCs that overexpressed AIMP3 under hypoxic conditions displayed significantly decreased proliferation and fewer stem cell characteristics, whereas the downregulation of AIMP3 ameliorated the age‐related senescence of MSCs. Consistent with the results of the hpMSCs, MSCs isolated from the adipose tissue of AIMP3‐overexpressing mice exhibited decreased stem cell functions. Interestingly, AIMP3‐induced senescence is negatively regulated by hypoxia‐inducible factor 1α (HIF1α) and positively regulated by Notch3. Furthermore, we showed that AIMP3 enhanced mitochondrial respiration and suppressed autophagic activity, indicating that the AIMP3‐associated modulation of metabolism and autophagy is a key mechanism in the senescence of stem cells and further suggesting a novel target for interventions against aging.

Adipose-Derived Mesenchymal Stem Cells Isolated from Patients with Abdominal Aortic Aneurysm Exhibit Senescence Phenomena

“…Growing evidence has shown that autophagy mediates the cellular senescence of MSCs [27, 28]. We first detected the autophagosomes in each cell using a TEM.…”

The novel interplay between CD44 standard isoform and the caspase-1/IL1B pathway to induce hepatocellular carcinoma progression

“…HIF1A is a crucial regulator in increasing autophagy and CSCs 47,48 . In hypoxic breast cancers, CD44s overexpression facilitates tumor proliferation and invasion by enhancing HIF1A signaling 32 .…”

Molecular Mechanisms Contributing to Mesenchymal Stromal Cell Aging

“…In human placental MSCs cultured in hypoxic conditions, the aging inducer aminoacyl-tRNA synthetase-interacting multifunctional protein 3 (AIMP3) was dramatically repressed with concurrent p16 downregulation. Moreover, AIMP3 enhances mitochondrial respiration and suppresses autophagy, while hypoxia-inducible factor 1α (HIF1α) inhibits AIMP3 [235]. Human urine stem cells (USCs), dental pulp stem cells (DPSCs), amniotic fluid stem cells (AFSCs), and BM-MSCs show enhanced cell proliferation rate, retention of stem cell properties, inhibition of senescence (as indicated by reduced SA-β-gal staining), and increased differentiation ability in hypoxic conditions compared to normoxia [236].…”